An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International

Abstract

Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use.

Keywords: ADPKD; polycystic kidney disease; position statement; tolvaptan; vasopressin V2 receptor antagonist.

FIGURE 1:

Extrapolations from the results of the (A) TEMPO 3:4 and (B) REPRISE trials allow estimations of the potential benefit of tolvaptan treatment in delaying the need for RRT (adapted from Chebib et al. [2]).

FIGURE 2:

Markers of disease progression and factors contributing to the information contained in these markers.

FIGURE 3:

Updated algorithm to assess (likely) fast disease progression as an indication for initiation of tolvaptan in ADPKD. This algorithm is only valid for individuals ≤55 years of age with an eGFR ≥25 mL/min/1.73 m² and a confirmed diagnosis of ADPKD. We do not recommend treatment in patients who do not fulfill these criteria. If alternative explanations for eGFR loss are likely (e.g. vascular disease, diabetic nephropathy), initiation of treatment should be reconsidered even in the presence of rapid eGFR decline. The following indicators point towards potential alternative explanations: proteinuria ≥1 g/day, signs for vascular disease (e.g. coronary heart disease, stroke), uncontrolled severe arterial hypertension and diabetes mellitus. In these cases, additional information [including MRI (CT) imaging if not performed before] should be acquired to ensure ADPKD as the primary reason for eGFR loss (see also Table 1): Mayo Class 1 C–E, PROPKD score >6, early hypertension/urological manifestations, truncating PKD1 mutation, family history (onset kidney replacement therapy <60 years in two or more first-line family members). Mayo Class 1C can be found in individuals without rapid disease progression. Consequently, we recommend obtaining additional information in these patients to confirm the prediction (e.g. observe patients to see whether they actually lose eGFR compatible with rapid disease progression) and/or obtain additional arguments for an initiation of treatment such as (see also Table 1): a PROPKD score >6, early hypertension/urological manifestations, truncating PKD1 mutation, family history (onset dialysis <60 years in two or more first-line family members).